Proteoglycans and Infectious Disease
A major effort is focused on the impact of heparan sulfate and chondroitin/dermatan sulfate on infection. We developed a vascular tagging method to measure how the endothelial proteome and glycoproteome change after bacterial challenge. A striking remodeling of the vascular proteome occurs in an temporally regulated and organotypic manner. Ongoing studies include analysis of the origin and function of vascular biomarkers in plasma, and their stratification according to infectious agent. We also are interested in bacterial toxins and their interaction with host cell proteoglycans. These studies are part of a collaboration with Victor Nizet’s lab and are funded through a Program Project Grant.
Another area of great interest these days concerns the role of glycosylation in COVID-19. We recently showed that SARS-CoV-2 infection depends on both heparan sulfate and ACE2 receptors. Current studies focus on the evolution of the heparan sulfate binding site in the spike proteins of coronaviruses, and host responses in glycosylation due to infection. A better understanding of the role of proteoglycans in these processes might define molecular targets for therapeutic intervention.
Relevant Papers
Pimienta, G., Heithoff, D.M., Rosa-Campos, A., Tran, M., Esko, J.D., Mahan, M.J., Marth, J.D., and Smith, J.W. (2019) Plasma proteome signature of sepsis: a functionally connected protein network. Proteomics 19:1800389-98. PMID:30706660 PMCID:6447370
Toledo, A.G., Golden, G., Campos, A.R., Cuello, H., Sorrentino, J., Lewis, N., Varki, N., Nizet, V., Smith, J.W. and Esko, J.D. (2019) Proteomic atlas of organ vasculopathies triggered by Staphylococcus aureus sepsis. Nat. Commun. 10:4656. PMID:31604940 PMCID:6789120
Clausen, T.M., Sandoval, D.R., Spliid, C.B., Pihl, J., Painter, C.D., Thacker, B.E., Glass, C.A., Narayanan, A., Majowicz, S.A., Zhang, Y., Torres, J.L., Golden, G.J., Porell, R., Garretson, A.F., Laubach, L., Feldman, J., Yin, X., Pu, Y., Hauser, B., Caradonna, T.M., Kellman, B.P., Martino, C., Gordts, P.L.S.M., Leibel, S.L., Chanda, S.K., Schmidt, A.G., Godula, K., Jose, J., Corbett, K.D., Ward, A.B., Carlin, A.F. and Esko, J.D. (2020) SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell 83:1043-1057. PMID: 32699853
Marki, A., Buscher, K., Lorenzini, C., Meyer, M., Saigusa, R., Fan, Z., Yeh, Y.T., Hartmann, N., Dan, J.M., Kiosses, W.B., Golden, G.J., Ganesan, R., Winkels, H., Orecchioni, M., McArdle, S., Mikulski, Z., Altman, Y., Bui, J., Kronenberg, M., Chien, S., Esko, J.D., Nizet, V., Smalley, D., Roth, J. and Ley, K. (2021) Elongated neutrophil-derived structures are blood-borne microparticles formed by rolling neutrophils during sepsis. J. Exp. Med. 218:e20200551. PMID:33275138
Golden, G.J., Toledo, A.G., Marki, A., Sorrentino, J.T., Morris, C., Riley, R.J., Spliid, C., Chen, Q., Cornax, I., Lewis, N.E., Varki, N., Le, D., Malmström, J., Karlsson, C., Ley, K., Nizet, V. and Esko, J.D.. (2021) Endothelial heparan sulfate mediates hepatic neutrophil trafficking and injury during Staphylococcus aureus sepsis. mBio 12:e0118121. PMID:34544271 PMCID:PMC8546592
Toledo, A.G., Sorrentino, J.T., Sandoval, D.R., Malmström, J., Lewis, N.E. and Esko, J.D. (2021) A systems view of the heparan sulfate interactome. J. Histol. Histochem. 69:105-119. PMID: 33494649